Transcranial Theranostic Ultrasound for Pre-Planning and Blood-Brain Barrier Opening: A Feasibility Study Using an Imaging Phased Array In Vitro and In Vivo

Batts, Alec J.; Ji, Robin; Kline-Schoder, Alina R.; Noel, Rebecca L.; Konofagou, Elisa E.

doi:10.1109/tbme.2021.3120919

Cited by 13 publications

(14 citation statements)

References 37 publications

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“…A repurposed P4-1 (ATL, Philips) imaging phased array (2.5 MHz center frequency, 1.5-3.5 MHz -6 dB bandwidth, 96 elements) was operated by a research ultrasound system (Vantage 256, Verasonics Inc., Kirkland, WA, USA) at a frequency of 1.5 MHz (Figure 1 A). A custom script was developed to combine power cavitation imaging (PCI) 30 and therapeutic focused transmits within the same transducer 40 , 43 . The multi-element phased array design facilitated electronic focusing and steering of the beam with a -6 dB focal volume consisting of axial, lateral and elevational dimensions of 12.40 mm, 1.12 mm, and 7.43 mm ( Figure S1 A-B), which permitted development of flexible short-pulse sequence designs for simultaneous BBB opening and cavitation mapping.…”

Section: Methodsmentioning

confidence: 99%

“…The three USPLs evaluated in this study, 1.5, 5, and 10 cycles were input as half-cycles (3, 10, and 20 half-cycles) as required by the Verasonics sequence programming interface (Figure 1 B). The RASTA sequence was immediately followed by a ~3 s period for GPU-based delay and sum beamforming, spatiotemporal clutter filtering, and PCI display and saving as previously reported 30 , 40 . Each emittance of the RASTA sequence, repeated at a burst repetition rate (BRF) of 0.33 Hz, generated PCI for each hemisphere (Figure 1 C) from which cavitation mapping pixel intensity was derived.…”

Section: Methodsmentioning

confidence: 99%

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Using a novel rapid alternating steering angles pulse sequence to evaluate the impact of theranostic ultrasound-mediated ultra-short pulse length on blood-brain barrier opening volume and closure, cavitation mapping, drug delivery feasibility, and safety

Batts¹,

Ji²,

Noel³

et al. 2023

Theranostics

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Background: Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is a noninvasive, safe and reversible technique for targeted drug delivery to the brain. Most preclinical systems developed to perform and monitor BBB opening are comprised of a separate geometrically focused transducer and passive cavitation detector (PCD) or imaging array. This study builds upon previous work from our group developing a single imaging phased array configuration for simultaneous BBB opening and monitoring called theranostic ultrasound (ThUS), leveraging ultra-short pulse lengths (USPLs) and a novel rapid alternating steering angles (RASTA) pulse sequence design for simultaneous bilateral sonications with target-specific USPL. The RASTA sequence was further employed to evaluate the impact of USPL on BBB opening volume, power cavitation imaging (PCI) pixel intensity, BBB closing timeline, drug delivery efficiency, and safety. Methods: A P4-1 phased array transducer driven by a Verasonics Vantage ultrasound system was operated using a custom script to run the RASTA sequence which consisted of interleaved steered, focused transmits and passive imaging. Contrast-enhanced magnetic resonance imaging (MRI) confirmed initial opening volume and closure of the BBB by longitudinal imaging through 72 hours post-BBB opening. For drug delivery experiments, mice were systemically administered a 70 kDa fluorescent dextran or adeno-associated virus serotype 9 (AAV9) for fluorescence microscopy or enzyme-linked immunosorbent assay (ELISA) to evaluate ThUS-mediated molecular therapeutic delivery. Additional brain sections were also H&E-stained to evaluate histological damage, and IBA1- and GFAP-stained to elucidate the effects of ThUS-mediated BBB opening on stimulation of key cell types involved in the neuro-immune response, microglia and astrocytes. Results: The ThUS RASTA sequence induced distinct BBB openings simultaneously in the same mouse where volume, PCI pixel intensity, level of dextran delivery, and AAV reporter transgene expression were correlated with brain hemisphere-specific USPL, consistent with statistically significant differences between 1.5, 5, and 10-cycle USPL groups. BBB closure after ThUS required 2-48 hours depending on USPL. The potential for acute damage and neuro-immune activation increased with USPL, but such observable damage was nearly reversed 96 hours post-ThUS. Conclusion: ThUS is a versatile single-array technique which exhibits the potential for investigating a variety of non-invasive therapeutic delivery applications in the brain.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Using a novel rapid alternating steering angles pulse sequence to evaluate the impact of theranostic ultrasound-mediated ultra-short pulse length on blood-brain barrier opening volume and closure, cavitation mapping, drug delivery feasibility, and safety

Batts¹,

Ji²,

Noel³

et al. 2023

Theranostics

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show abstract

“…Based on the therapeutic goal, the target region, dose and FUS parameters can be modified to maximize the transport of AAV into the brain. We previously developed two different FUS systems, spherical single-element FUS 3 and FUS array, 4 enabling transient opening of the BBB in a more confined or widespread region, respectively (Fig. 1b).…”

Section: Figmentioning

confidence: 99%

Focused ultrasound-mediated brain genome editing

Lao

Zhou

et al. 2022

Preprint

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Gene editing in the mammalian brain has been challenging because of the restricted transport imposed by the blood-brain barrier (BBB). Current approaches rely on local injection to bypass the BBB. However, such administration is highly invasive and not amenable to treating certain delicate regions of the brain. We demonstrate a safe and effective gene editing technique by using focused ultrasound (FUS) to transiently open the BBB for the transport of intravenously delivered CRISPR/Cas9 machinery to the brain.

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“…Landmark-based registration of vascular maps created with MRI and Doppler ultrasound revealed BBB opening inside the intended focus with targeting accuracy within 1.5 mm. Combined use of power Doppler imaging with passive acoustic mapping demonstrates an ultrasound-based solution to guide focused ultrasound with high precision in rodents.Focused ultrasound (FUS), when paired with microbubbles (MBs), can open blood brain barrier (BBB) reversibly and safely in animal models [1][2][3][4] . Opening BBB with FUS can help in successfully transporting various drug molecules such as doxorubicin and neurturin across BBB in small animals and can further enhance treatment of brain tumors and provide neuroprotection for Parkinson's disease 5,6 .…”

mentioning

confidence: 99%

“…Focused ultrasound (FUS), when paired with microbubbles (MBs), can open blood brain barrier (BBB) reversibly and safely in animal models [1][2][3][4] . Opening BBB with FUS can help in successfully transporting various drug molecules such as doxorubicin and neurturin across BBB in small animals and can further enhance treatment of brain tumors and provide neuroprotection for Parkinson's disease 5,6 .…”

mentioning

confidence: 99%

Guiding and monitoring focused ultrasound mediated blood–brain barrier opening in rats using power Doppler imaging and passive acoustic mapping

Singh

Kusunose

Phipps

et al. 2022

Sci Rep

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The blood–brain barrier (BBB) prevents harmful toxins from entering brain but can also inhibit therapeutic molecules designed to treat neurodegenerative diseases. Focused ultrasound (FUS) combined with microbubbles can enhance permeability of BBB and is often performed under MRI guidance. We present an all-ultrasound system capable of targeting desired regions to open BBB with millimeter-scale accuracy in two dimensions based on Doppler images. We registered imaging coordinates to FUS coordinates with target registration error of 0.6 ± 0.3 mm and used the system to target microbubbles flowing in cellulose tube in two in vitro scenarios (agarose-embedded and through a rat skull), while receiving echoes on imaging transducer. We created passive acoustic maps from received echoes and found error between intended location in imaging plane and location of pixel with maximum intensity after passive acoustic maps reconstruction to be within 2 mm in 5/6 cases. We validated ultrasound-guided procedure in three in vivo rat brains by delivering MRI contrast agent to cortical regions of rat brains after BBB opening. Landmark-based registration of vascular maps created with MRI and Doppler ultrasound revealed BBB opening inside the intended focus with targeting accuracy within 1.5 mm. Combined use of power Doppler imaging with passive acoustic mapping demonstrates an ultrasound-based solution to guide focused ultrasound with high precision in rodents.

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Transcranial Theranostic Ultrasound for Pre-Planning and Blood-Brain Barrier Opening: A Feasibility Study Using an Imaging Phased Array In Vitro and In Vivo

Cited by 13 publications

References 37 publications

Using a novel rapid alternating steering angles pulse sequence to evaluate the impact of theranostic ultrasound-mediated ultra-short pulse length on blood-brain barrier opening volume and closure, cavitation mapping, drug delivery feasibility, and safety

Using a novel rapid alternating steering angles pulse sequence to evaluate the impact of theranostic ultrasound-mediated ultra-short pulse length on blood-brain barrier opening volume and closure, cavitation mapping, drug delivery feasibility, and safety

Focused ultrasound-mediated brain genome editing

Guiding and monitoring focused ultrasound mediated blood–brain barrier opening in rats using power Doppler imaging and passive acoustic mapping

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